U.S. Pat. No. 4,710,500 corresponding to EP 200,322B, discloses in general optionally 5-substituted 1-aryl-3-(4-piperidyl)--(I'), 1-aryl-3-(1-piperazinyl)--(II) or 1-aryl-3-(1,2,3,6-tetrahydro-4-pyridyl)-indole (III) derivatives having the formulas: ##STR3## in which formulas R' designates optionally substituted phenyl or a hetero aromatic group, R.sup.1' is hydrogen or a substituent such as halogen, alkyl, alkoxy, cyano, nitro, etc, and R.sup.2' is hydrogen, alkyl, alkenyl or a certain heterocycle-lower alkyl substituent.
Most of the compounds are shown to be potent and long-lasting dopamine antagonists in vivo, and accordingly to be useful in the treatment of psychoses and all the compounds are proven to be strong serotonin-S.sub.2 (5-hydroxytryptamine-2; 5-HT.sub.2) receptor antagonists in vivo indicating effects in the treatment of depression and negative symptoms of schizophrenia. The tests used to show blockade of dopaminergic activity in vivo were a catalepsy test and a methylphenidate test, both being at that time regarded as tests for dopaminergic activity. However, at present said two tests are considered also to be a measure of the propensity of an antipsychotic compound to induce extrapyramidal side effects.
Though U.S. Pat. No. 4,710,500 generally comprises the 3-(4-piperidyl) compounds of the Formula I' disclosed above, only five such compounds have been specifically disclosed, i.e. 1-(4-fluorophenyl)-5-methyl-3-(1-methyl-4-piperidyl)-1H-indole, hydrobromide, designated Lu 21-037, 1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperidyl]-1H-i ndole, designated Lu 23-086, 1-(4-fluorophenyl)-3-[1-[2-(2-pyrrolidinon-1-yl)ethyl]-4-piperidyl]-5-trif luoro-methyl-1H-indole, fumarate, designated Lu 23-158, 1-(4-fluorophenyl)-3-(1-methyl-4-piperidyl)-5-trifluoromethyl-1H-indole oxalate, designated Lu 21-131, 5-chloro-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperi dyl]-1H-indole, sertindole.
The compound sertindole which is the compound of the above Formula I' wherin R.sup.1' is chloro, R' is 4-fluorophenyl and R.sup.2' is 2-(2-imidazolidinon-1-yl)ethyl is a known neuroleptic, the neuroleptic activity of which is described in the co-pending U.S. patent application Ser. No. 07/508,240 corresponding to EP 392,959A.
Our copending International Patent Application Publ. No. WO 92/00070 discloses the 3-(4-piperidyl) compounds of the formula I' as having anxiolytic activity without cataleptic activity and our copending International Patent Application No. PCT/ DK91/00291 describes prodrugs of sertindole.
Addiction with physical and psychological dependence to drugs such as cocaine, opiates, benzodiazepines, etc, and abuse of alcohol and nicotine and other substances causes great social and health problems all over the world. When the drug or substance of abuse is withdrawn from a dependant subject the subject develops physical and psychological withdrawal symptoms such as aggressive behaviour, agitation and intense craving for the drug or substance of abuse. Accordingly, withdrawal of such substances from addicts and abusers is very difficult, and no effective treatment of withdrawal symptoms and accordingly method of obtaining withdrawal is at present available. Accordingly, a compound which inhibits withdrawal symptoms or suppress dependence of drugs and other substances of abuse is highly desirable.
Surprisingly, it has now been found that certain 1-aryl-3-(4-piperidyl)-indole derivatives having the above general Formula I' in addition to the 5-HT.sub.2 receptor antagonistic activity, also have alleviating, relieving or suppressing properties on withdrawal or abstinence symptoms and that they suppress the dependency of drug or substance of abuse. Furthermore they have been found to be non-cataleptic.